Before the discovery and development of antibiotics, death due to a bacterial infection was frequently rapid and inevitable. Gram-positive multiresistant bacteria, such as Staphylococcus aureus and Enterococci , are among the major nosocomial pathogens and are responsible for numerous deaths and extended hospital stays of patients.
The cell walls of Gram-positive bacteria contain three major components: peptidoglycan, capsular polysaccharides, and teichoic acids plus additional carbohydrates, glycoconjugates and proteins depending on the species.
Of the Gram-positive bacteria, one of the most common genera is Staphylococcus. Staphylococci commonly colonize humans and animals and are an important cause of human morbidity and mortality, particularly in hospitalized patients. Staphylococci are prevalent on the skin and mucosal linings and, accordingly, are ideally situated to produce both localized and systemic infections.
Staphylococcal infections are difficult to treat for a variety of reasons. Resistance to antibiotics is common and becoming more so, due to transferrable methicillin and multidrug resistance. In addition, host resistance to Staphylococcal infections is still not clearly understood.
Opsonic antibodies have been proposed to prevent or treat Staphylococcal infections. See, for example, U.S. Pat. No. 5,571,511.
Enterococci are Gram-positive cocci that often occur in pairs (“diplococcus”) or short chains, and are difficult to distinguish from “Streptococcus” on physical characteristics alone. Two species are common commensal organisms in the intestines of humans: E. faecalis (90-95%) and E. faecium (5-10%).
Important clinical infections caused by Enterococcus include urinary tract infections, bacteremia, bacterial endocarditis, diverticulitis, and meningitis. From a medical standpoint, an important feature of this genus is the high level of intrinsic antibiotic resistance. Some enterococci are intrinsically resistant to β-lactam-based antibiotics (penicillins, cephalosporins, carbapenems), as well as many aminoglycosides. In the last two decades, particularly virulent strains of Enterococcus that are resistant to vancomycin (vancomycin-resistant Enterococcus, or VRE) have emerged in nosocomial infections of hospitalized patients, especially in the US.
U.S. Pat. No. 4,578,458 describes a method of inducing an immune response against multiple strains of (the Gram-negative bacterium) Pseudomonas aeruginosa which comprises administering to a human or animal an amount of mucoid exopolysaccharide from Pseudomonas aeruginosa 2192 sufficient to induce an immune response in the human or animal is disclosed along with the microorganism which produces this antigen and a method of separating the antigen from the crude bacterial slime. Thus, a vaccine capable of inducing an immune response against multiple strains of Pseudomonas aeruginosa is provided. A minimum preferred amount is the amount required to elicit antibody formation to a concentration at least 4 times that which existed prior to administration.
U.S. Pat. No. 7,230,087 further describes peptides, particularly human monoclonal antibodies, that bind specifically to Pseudomonas aeruginosa mucoid exopolysaccharide. The invention further provides methods for using these peptides in the diagnosis, prophylaxis and therapy of Pseudomonas aeruginosa infection and related disorders (e.g., cystic fibrosis). Some antibodies of the invention enhance opsonophagocytic killing of multiple mucoid strains of Pseudomonas aeruginosa. Compositions of these peptides, including pharmaceutical compositions, are also provided, as are functionally equivalent variants of such peptides.
U.S. Pat. No. 5,233,024 describes an anti-idiotypic monoclonal antibody, which is opsonic for mucoid Pseudomonas aeruginosa. The anti-idiotypic monoclonal antibody is produced by a cell line designated C9F5 and having ATCC accession No. HB10715. The anti-idiotypic monoclonal antibody is useful as a vaccine and for diagnostic purposes.
WO 1998/57994 describes monoclonal and chimeric antibodies that bind to lipoteichoic acid of Gram-positive bacteria. The antibodies also bind to whole bacteria and enhance phagocytosis and killing of the bacteria in vitro and enhance protection from lethal infection in vivo. Here, a mouse monoclonal antibody that has been humanized is described. The publication also encompasses a peptide mimic of the lipoteichoic acid epitope binding site defined by the monoclonal antibody.
WO 2003/059260 discloses monoclonal antibodies that bind to lipoteichoic acid LTA of Gram-positive bacteria. The antibodies also bind to whole bacteria and enhance phagocytosis and killing of the bacteria in vitro. Described are also antibodies having human sequences chimeric, humanized and human antibodies.
EP2476702 A1 discloses monoclonal antibodies able to recognize and bind to PBP2a protein and other proteins presenting sequences homologous to PBP2a, including the pathogens methicillin-resistant Staphylococcus aureus—MRSA, coagulase-negative Staphylococcus, Staphylococcus sciuri, Enterococcus spp., and any other bacterium possessing PBP2a or sequences homologous to this protein. PBP2a is a class II multimodular enzyme anchored in the membrane of the bacteria and responsible for the bacterial transpeptidation reactions when synthesizing murein. The protection conferred by the treatment with monoclonal antibody caused a reduction of 89 times in the quantity of bacteria present in the kidneys of animals treated, which was higher than the protection obtained with the treatment with 5 vancomycin doses (reduction of 35 times). However, the most significant reduction result was seen in the group treated with antibody+vancomycin, causing a reduction of 450 times.
Theilacker et al. (in: Protection against Staphylococcus aureus by antibody to the polyglycerolphosphate backbone of heterologous lipoteichoic acid (LTA). J Infect Dis. 2012 Apr. 1; 205(7):1076-85) describe that antibodies against E. faecalis LTA also bind to type 1 LTA from other gram-positive species and opsonized Staphylocccus epidermidis and Staphylcoccus aureus strains as well as group B streptococci. Passive immunization with rabbit antibodies against E. faecalis LTA promoted the clearance of bacteremia by E. faecalis and S. epidermidis in mice. LTA is proposed as conserved bacterial structure that could function as a single vaccine antigen that targets multiple gram-positive pathogens.
WO 2005/103084 discloses human monoclonal antibodies that bind specifically to poly-N-acetyl glucosamine (PNAG), such as Staphylococcal PNAG, in acetylated, partially acetylated and/or fully deacetylated form. The antibodies can be used in the diagnosis, prophylaxis and therapy of infections by bacteria that express PNAG such as to Staphylococci and E. coli. Some antibodies of the invention enhance opsonophagocytic killing and in vivo protection against bacteria that express PNAG such as Staphylococci and E. coli. 
WO 2007/141278 discloses single chain Fv fragments specifically binding to enterococci that are selected from scFv phage display libraries. An opsonophagocytic assay was conducted to quantify the killing activity of anti-enterococci human IgG1 against the enterococcal clinical isolate 12030. None of the antibodies as tested showed binding to lipoteichoic acid (LTA) of S. aureus. 
The above state of the art shows that attempts were undertaken to produce more or less effective antibodies against a quite large variety of components of the cell wall of Gram-positive bacteria. Nevertheless, neither the target(s) nor the effectiveness of any of these antibodies in the protection against infections could be reliably predicted in advance.
There is a need in the art to provide new and effective monoclonal antibodies that can bind to Staphylococcus with higher affinity, and that can enhance phagocytosis and killing of the bacteria and thereby enhance protection in vivo. For the development of mAbs it would be advantageous to choose variable domains that recognize cross-reactive antigens to cover a broad spectrum of pathogens. There is a related need for humanized or other chimeric human/mouse monoclonal antibodies, and respective uses thereof in the treatment of Gram-positive infections.